It was March 2020 and Ash was the healthiest she’d been in 15 years. She had just started an exciting new job and COVID was still a nameless “novel coronavirus” mainly appearing on cruise ships. One evening, after getting home from the gym, Ash was suddenly struck with a wave of feverish delirium. She passed out and eventually came to a couple of hours later on the kitchen floor with her dog staring down at her.

The next two weeks were a blur, but eventually Ash started to feel better. About a month after the initial illness she had pretty much recovered. And then things started getting strange. She had this feeling her teeth were rotting. A painful pressure began building in her head.

“And it just took over my nerves,” Ash explained in a conversation with Salon. “About six weeks after COVID, I started losing the use of my hands.”

Everything from opening a ziploc bag to using scissors became profoundly difficult. Multiple GPs, dentists, clinical specialists and even a Chinese acupuncturist all had no idea what was going on. By the end of 2020 Ash had stopped working altogether. Alongside the neuropathic problems all the now common neurological long COVID issues had become entrenched: Brain fog, dissociation, extreme fatigue, memory troubles.

Alienated by mainstream medicine’s denial of her condition, Ash became her own guinea pig for the next couple of years. With a deep knowledge of science and a pool of friends in the entheogenic community Ash tried anything and everything to overcome her debilitating symptoms. Steroids, low-dose naltrexone, melatonin, lecithin, goldenseal, sceletium and a whole world of anti-inflammatory botanical ferments like kefir. Some helped temporarily, some didn’t help at all. Ash kept a detailed treatment diary, tracking the effects of everything she consumed.

“People were just sending me random obscure stuff. And I'm like, yep, that doesn't work. That works. That doesn't work. Oh, that doesn't work for more than three days.”

Then in early 2023, Ash tried something completely different. Something she described as a game-changer for her condition: A powerful hallucinogenic plant called iboga that originates from Africa. It's active ingredient is known as ibogaine and it's being explored for addiction treatment. It's not clear yet if it will really help — but even more questions remain about its potential for alleviating long COVID.

The serotonin hypothesis

It has been estimated that at least 65 million people have, or have had, long COVID. The illness encompasses hundreds of different symptoms and researchers are still struggling to find a way to easily define it. Some of the more universal symptoms — fatigue, post-exertional malaise, brain fog or memory loss — resemble what has previously been seen in other post-viral chronic illnesses, such as influenza or Epstein-Barr. But the sheer scale and heterogeneity of long COVID has made it challenging to study.

A number of different, compelling hypotheses have emerged to try and describe the pathology underlying long COVID. Some have suggested the condition is caused by a persistent viral reservoir of SARS-CoV-2 viruses, the microbes that cause COVID, hiding out somewhere in the body. Others argue the acute illness triggers a chain reaction of immune dysregulation, which ultimately leads to persistent chronic symptoms. It’s also been proposed that SARS-CoV-2 could alter one’s gut microbiome in ways that cause broader systemic inflammation. And then there’s all the ways COVID can impair normal functions of the brainstem and vagus nerve.

In October a study was published in the journal Cell that turned the world of long COVID research upside down. The study, led by a team from Perelman School of Medicine at the University of Pennsylvania, presented a kind of grand-unifying hypothesis attempting to tie together all prior ideas surrounding long COVID.

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The researchers first reviewed metabolite profiles from several previously published long COVID studies. A pattern quickly emerged. Those patients with long-term symptoms consistently showed lower levels of circulating serotonin. In fact, the pattern was so reliable the researchers could distinguish long COVID patients from fully recovered patients just by measuring plasma serotonin levels.

Subsequent animal tests revealed SARS-CoV-2 infections did indeed reduce circulating serotonin — so the researchers then wondered how this was happening. Because the vast majority of serotonin in our body is produced in the gastrointestinal tract, all attention turned to the gut.

Across a series of impressive animal and organoid experiments the researchers discovered SARS-CoV-2 infections induced a kind of inflammatory response that disrupted the gut’s ability to absorb the amino acid tryptophan. Without an effective source of tryptophan the GI tract is unable to effectively produce serotonin, and this is potentially how serotonin depletion could be a defining trait of long COVID.

The final piece of the puzzle was understanding how this viral-induced serotonin depletion could lead to the neurocognitive problems commonly seen in long COVID. After all, serotonin produced in the gut does not cross the blood-brain barrier. While circulating serotonin levels looked to be directly depleted by viral inflammation, levels of serotonin in the brain remained unaffected.

Here the researchers turned to the vagus nerve — a crucial communication superhighway that travels from the brainstem to the gut. It was discovered serotonin depletion in the gut dampened vagal nerve signalling to the brain, specifically the hippocampus. When vagal nerve activity was reduced, hippocampal neuron activity declined, and this led to cognitive impairments such as memory problems.

The masterstroke in the new research was its exploration into how serotonin interacts with vagal nerve neurons. Elaborate animal and cell tests revealed serotonin signalling via 5HT3 receptors on vagal nerve neurons was responsible for this whole chain reaction. And, perhaps most significantly, when 5HT3 receptors on the vagal nerve were artificially stimulated with a drug, animals suffering long COVID-like impairments showed notable cognitive improvements.

What psychedelic compound is known to stimulate 5HT3 receptors? Ibogaine.

No magic bullet

Ash was fastidious about maintaining a treatment diary. “Start low, go slow”, she’d say in reference to bringing any new compound into her larger regime. In the merry-go-round of self-experiments she looked to a homegrown iboga tincture. Maybe, in low doses, it could help give her the motivation to exercise, she thought.

“Some people are extremely responsive to iboga,” Ash said. “It has adverse effects when I take a drop of the homemade tincture without diluting it down.”

These minidoses of iboga did help Ash start exercising regularly again. They weren’t traditional microdoses but something closer to a psychedelic dose. The psychological boost from this motivational bounce sent positive ripples throughout the rest of his life, but the iboga was no panacea. The brain fog and sense of disconnectedness was still devastating. Ash would regularly spend hours just staring into space.

Some time passed and a colleague offered Ash a magic mushroom extract. It was an unpleasant-tasting homemade concoction but being the psychonaut scientist she is, Ash gave it a shot. She took a minidose of the extract. The result was a deep healing sleep and Ash was excited. She took another small dose the very next day but it frustratingly did nothing.

She called her colleague with the news about the inconsistent results. “No, no, no,” the colleague said. “You can only take this once or twice a week.”

“So I eyeballed a dose twice a week,” Ash said. “And the mental clarity started to come back. And they kind of feed off each other. So if you've got enough physical energy to do something, then you can exercise, you can go outside, you can have a shower, wash your clothes, you can hang them up. And you can do that best if you've had a deep night's sleep, which I hadn't had for a long time.”

The magic mushroom extract helped Ash regain a substantial volume of mental clarity and connectedness. Like any chronic disease, improvements were gradual with frequent relapses. Two steps forward, one step back, as they say.

“[But there] was still a feeling of derealization, depersonalization,” Ash said. “Things aren't connected to each other, like being hungry and having food in the house are two completely separate issues. [And] it can take you an hour to connect.”

So Ash began experimenting with DMT. Just once or twice a month in a smokable blend commonly known as changa. Much like Ash’s prior psychedelic experiments, the DMT was imbibed in low doses.

“I wasn't out to discover the meaning of life. I just wanted to get far enough in that I could access reality on a step by step basis. You can't afford to be that far gone if you're not processing things properly. If you can't remember how to put a meal together, the last thing you want to be is crawling around the floor.”

The psilocybiome

“The gut microbial system, at the interface between the individual and the environment, is important for healthy homeostasis,” explained John Kelly, a psychiatrist and neuroscientist from Trinity College Dublin. “Gut microbes communicate with the brain via the gut-brain axis, including tryptophan-kynurenine, immune, hypothalamic pituitary adrenal axis, and vagus nerve pathways.”

Kelly has worked on several psychedelic therapy clinical trials, including last year’s landmark phase 2 human study exploring the effect of single psilocybin doses on treatment-resistant depression. However, one of his personal areas of interest looks to bring together two different nascent scientific fields — psychedelic medicine and the microbiome.

In late 2022 Kelly and colleagues published a curious paper that proposed a novel hypothesis. If the trillions of microbes in our gut are being found to play a role in everything from psychiatric disorders to autoimmune disease, then what effect do these biofeedback signals have on the therapeutic outcomes of psychedelic medicine? Here Kelly and colleagues coined the term “psilocybiome,” a combination of the words psilocybin and microbiome

“The term ‘psilocybiome’ is still somewhat conceptual at this point, but broadly refers to the interaction between psychedelics and the microbiota-gut-brain axis,” says Kelly. “In other words, the psilocybiome comprises the reciprocal host-microbiota-psychedelic interactions and serves as an example of systems interconnectivity.”

Almost all questions surrounding the effect of psychedelics on gut-brain communications remain unanswered. In fact, both worlds of psychedelic and microbiome science are filled with countless unknowns right now. So much so that most reasonable scientists are incredibly cautious when talking about these things.

“It is established that serotonergic psychedelics have immunomodulator and anti-inflammatory properties,” Kelly said. But the precise immune-signalling pathways and their relationship to the vagus nerve as related to potential therapeutic effects “have yet to be fully understood.”

Kelly says the serotonin hypothesis for long COVID is a commendable piece of translational research. It points to fascinating directions for future research into the effects of serotonergic psychedelics on the gut.

The traditional psychoactive brew ayahuasca, which contains the powerful psychedelic DMT, for example, is well known for its unpleasant physical effects. Nausea and vomiting are consistently reported to precede the brew’s hallucinogenic onset.

Scientists have suggested the purging associated with ayahuasca is the result of a flush of serotonin released by the gut. This serotonin release then stimulates the vagus nerve causing the acute vomiting that accompanies the experience.

Attila Szabo, from the University of Oslo, is perhaps one of the world’s top experts on the immune modulating effects of psychedelics. He says the recently published serotonin hypothesis for long COVID is “outstanding” and “exciting”, but he also warns against self-experimentation with psychedelics, even for post-acute sequelae of COVID-19, or PASC, another name for long COVID.

“I can see the beauty of a hypothesis on testing the potential therapeutic effects of e.g. microdosing classic psychedelics to tackle the pathophysiology of decreased systemic serotonin in PASC. However, we desperately need more human clinical studies, before any recommendations could be formulated here,” Szabo explained in an email to Salon.

According to Szabo, we have very little understanding of the systemic immune effects of psychedelics in humans. And in some cases psychedelics could hypothetically be harmful.

“This is something that everybody needs to understand: Until the first reliable human clinical data is getting published, self-experimenting with psychedelic substances to treat inflammation, autoimmune disorders, symptoms of PASC, etc. is clearly not advised. Since classic psychedelics can also potentially cause system-level immunosuppression (both short and long-term, depending on drug use habits and other factors), avoiding them in the chronic phase of a disease seems to be wise,” Szabo stressed.

Kelly agrees, even indicating a need for further preclinical work to better home in on the complex interactions between psychedelics, the immune system and the psilocybiome. One compelling point Kelly makes is that psychedelic medicine generally focuses on the acute effects of a small handful of big doses. Other medicines, such as antidepressants, are taken daily for months, or even years, so their effects can be more consistent. Does one big dose of psilocybin lead to persistent benefits when thinking about conditions like long COVID, or will we need to explore longer-term low-doses?

“It is important to consider the different durations of treatment between SSRIs or tryptophan supplementation and the serotonergic psychedelics,” Kelly explains. “Clinical studies typically use between 1 and 3 doses of psychedelic in the context of therapy. As such, it will be interesting to figure out the extent to which 1 – 3 doses of psychedelic would be mediated by the pathways of the microbiota-gut-brain axis in post viral conditions, such as long COVID and other immune-dysregulated conditions.”

A search for more scientific evidence

Saleena Subaiya is an assistant professor at Columbia University's Department of Psychiatry whose personal long COVID story started in early 2021. The condition forced them to quit their job as an emergency room physician in a busy New York hospital. Like many long COVID patients, they faced doctors who dismissed their condition as unrelated to COVID. They were put on numerous medical treatments, both traditional and non-traditional. Ultimately, Subaiya found their own way to live with long COVID. Diet and lifestyle changes were crucial, but to this day they still have good and bad days.

Over the last couple of years their interest in the potential for psychedelic medicines to treat long COVID led them to establish the first human clinical work directly investigating the relationship. Subaiya is currently running two human trials, one in the middle of recruitment and the other beginning in the new year. These initial trials are small pilot studies looking primarily at the effects of certain psychedelics on psychiatric and neurocognitive symptoms associated with long COVID.

Echoing Szabo and Kelly, Subaiya is well-aware of how uncharted this territory is. Long COVID is a new illness, still being fully understood. Psychedelic medicine is a nascent field, with so much yet to be learned.

“You can understand how having a novel disease with a novel mechanism that we're still trying to figure out, as well as trying to use novel therapeutics, ones that have been illegal for many years and are still illegal, presents a challenge,” Subaiya explained in an interview with Salon. “And so it's really, really important that we proceed very carefully. And we don't over promise when the data is burgeoning.”

Subaiya says the recently proposed serotonin model for long COVID is exciting, and points to a potential way some psychedelics could help some patients. But from their experience the heterogeneous nature of long COVID means this hypothesis is unlikely to encompass all presentations of the illness. They cited patients with long COVID-like symptoms from post-vaccine injury as a good example.

“So these patients present with a similar constellation of long COVID symptoms, but they don't actually have viral persistence,” they explained. “And so this could be one theory that explains a portion of the patients that have chronic fatigue, brain fog, etc. But I'm not entirely sure that this presents the entire picture.”

One of Subaiya’s biggest concerns for long COVID patients who may be experimenting with psychedelics is the possibility of their condition getting worse. Post-exertional malaise is a hallmark of long COVID for many patients. This is where cognitive, physical or emotional exertion causes a flare-up in disease symptoms.

“So we know that serotonergic hallucinogens can create a very, very intense and powerful psychological experience. When you're taxing the body, it can possibly even be detrimental to patients, if in fact, they're having a fearful experience. They're not adequately prepared. They don't have a provider to walk them through some of the bigger questions that can result after these experiences that can create ongoing stress. These are all really, really critical.”

“There is no quick fix”

“I can confidently say now I'm probably 90% back,” Ash said. “I can ride my motorcycle short distances. I'm not waking up with facial bruising in the morning. I can use scissors. I can memorize six digit strings of numbers. I still can't play guitar. I can't lift anything over my head. There’s a bunch of stuff I can't do. But looking back on where I was in May 2020 it's a much more fabulous place.”

For Ash psychedelics were crucial to her slow recovery, but they were also part of a larger therapeutic regime. A regime that included changes to diet, exercise, lifestyle. A regime that included countless experiments with other botanicals, herbs and vitamins.

Subaiya certainly believes in the potential for psychedelics to play a therapeutic role in the treatment of long COVID. However they are still struck with so many questions that they urge people to not start self-experimenting.

What specific psychedelics could benefit long COVID patients? What particular populations of long COVID should be targeted? What kinds of doses help? What kinds of doses harm? These are all questions with no good answers right now.

“We're in a mental health crisis,” Subaiya said. “We want a quick fix. And the answer is that there is none. We need a holistic model of care that takes into account the individual, their medical needs, their psychological needs, their unique cultural backgrounds, all of those things are so critical. Because of the hype around psychedelics, because there's no treatment for long COVID, we have a vulnerable population that is desperately seeking a treatment. And this concern that I have is that the data is just not there yet. And so, you know, it's really, really important to proceed cautiously.”

From Ash’s perspective she is cautious to recommend anything specific to anyone. She recognizes the privilege she had in terms of both having access to a community of scientists and plant experts, and the space to develop a personal treatment regime.

“I'm really lucky to be from that generation of Psychonauts, who considers holistic medicine to be diet, exercise, lifestyle, self reflection, documentation. Taking care with these things, you can't really separate anything out.”

And her advice to anyone with long COVID is to remove as many stresses from your life and be gentle on yourself.

“Pick one thing, start low, go slow, and monitor it. Whether it's diet, exercise, meditation, medication, or psychedelics.”